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The identical leucine\u2010to\u2010proline (L16P) amino acid substitution in PMP22 is carried by the Trembler J (TrJ) mouse and is found in CMT1E patients presenting with early\u2010onset disease. Peripheral nerves of patients diagnosed with CMT1E display a complex and varied histopathology, including Schwann cell hyperproliferation, abnormally thin myelin, axonal degeneration, and subaxonal morphological changes. Here, we have taken an unbiased data\u2010independent analysis (DIA) mass spectrometry (MS) approach to quantify proteins from nerves of 3\u2010week\u2010old, age and genetic strain\u2010matched wild\u2010type (Wt) and heterozygous TrJ mice. Nerve proteins were dissolved in lysis buffer and digested into peptide fragments, and protein groups were quantified by liquid chromatography\u2010mass spectrometry (LC\u2013MS). A linear model determined statistically significant differences between the study groups, and proteins with an adjusted p\u2010value of less than 0.05 were deemed significant. This untargeted proteomics approach identified 3759 quality\u2010controlled protein groups, of which 884 demonstrated differential expression between the two genotypes. Gene ontology (GO) terms related to myelin and myelin maintenance confirm published data while revealing a previously undetected prominent decrease in peripheral myelin protein 2. The dataset corroborates the described pathophysiology of TrJ nerves, including elevated activity in the proteasome\u2010lysosomal pathways, alterations in protein trafficking, and an increase in three macrophage\u2010associated proteins. Previously unrecognized perturbations in RNA processing pathways and GO terms were also discovered. Proteomic abnormalities that overlap with other human neurological disorders besides CMT include Lafora Disease and Amyotrophic Lateral Sclerosis. Overall, this study confirms and extends current knowledge on the cellular pathophysiology in TrJ neuropathic nerves and provides novel insights for future examinations. Recognition of shared pathomechanisms across discrete neurological disorders offers opportunities for innovative disease\u2010modifying therapeutics that could be effective for distinct neuropathies.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16189-fig-0009-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16189","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T04:24:53Z","timestamp":1722227093000},"page":"3154-3170","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Quantitative proteomics unveils known and previously unrecognized alterations in neuropathic nerves"],"prefix":"10.1111","volume":"168","author":[{"given":"Victoria","family":"Defilippi","sequence":"first","affiliation":[{"name":"Department of Physiology and Cell Biology, School of Medicine University of Nevada, Reno  Reno Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juli","family":"Petereit","sequence":"additional","affiliation":[{"name":"Nevada Bioinformatics Center (RRID:SCR_017802) University of Nevada, Reno  Reno Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie J. L.","family":"Handlos","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, School of Medicine University of Nevada, Reno  Reno Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6373-9713","authenticated-orcid":false,"given":"Lucia","family":"Notterpek","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, School of Medicine University of Nevada, Reno  Reno Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,7,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2017.12.021"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.02.022"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24386"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020106389"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.12.046"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.10-06-01855.1990"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90183-D"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.106"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.6160.1"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pmrj.2013.08.611"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-33-10672.2003"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1558981"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-021-01145-z"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.180801"},{"issue":"111","key":"e_1_2_10_17_1","article-title":"Targeted data extraction of the MS\/MS spectra generated by data\u2010independent acquisition: A new concept for consistent and accurate proteome analysis","volume":"11","author":"Gillet L. 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